生物活性

• 靶点

  IGF-1R IC50:1.8nM

  Insulin Receptor IC50:1.7nM

• 描述IGF-1R (insulin-like growth factor-1 receptor) plays a key role in transformation, growth and survival of malignant cells, and has been considered as a general and promising target for cancer treatment. BMS-754807 is a multi-target tyrosine kinase inhibitor, most potent to IGF-1R and IR with IC50 values of 1.8nM and 1.7nM, as well as showed less potency to Met, RON, TrkA, TrkB, AurA, and AurB with IC50 values of 6, 44, 7, 4, 9, and 25nM, respectively^[1]. BMS-754807 could inhibit the phosphorylation of IGF-1R and the downstream AKT and MAPK (ERK) with IC50 values of 13nM, 22nM and 13nM, as well as showed anti-proliferation with IC50 of 7nM in IGF-Sal cell line^[2]. BMS-754807 at concentration of 50nM for >4h induced apoptosis, shown by cleaved PARP and Caspase 3 as well as sub-G1 arrest, in Rh41 cells. BMS-754807 exhibited inhibition on cell growth of a broad range of tumor cell lines of various histologic origins including Ewing's, rhabdomyosarcoma, neuroblastoma, liposarcoma, breast, lung, pancreatic, colon, gastric, multiple myeloma and leukemia, with IC50 ranging in 5-365nM in most cell lines. Consistent with this, BMS-754807 showed in vivo antitumor activity in various preclinical tumor models in mice and efficient to a selected group of epithelial (IGF-1R-Sal, GEO, and Colo205), hematopoietic (JJN3), and mesenchymal (RD1 and Rh41) xenograft tumor models with tumor growth inhibition ranging in 53% to 115% after oral administration of BMS-754807 at dose ranging in 3.1-50mg/kg. As BMS-754807 inhibited both IGF-1R and IR, an oral glucose tolerance test showed that increased serum glucose level to 1.1-1.6 fold within 1h posttreatment could be observed in rodents dosed of 3.125 and 12.5mg/kg BMS-754807 at 30min before glucose challenge, with remained elevated insulin level by 2h posttreatment^[1].
• 作用机制BMS-754807 is a reversible ATP-competitive antagonist of IGF-1R and inhibits the catalytic domain of the IGF-1R.^[2]

• 动物研究
  剂量	Nude Mice: 3.125mg/kg - 25 mg/kg[1] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Nude mice[1] Dose 6.25 mg/kg Administration p.o. Cmax 71 nmol/L Tmax 0.5 h